The long-term goal of our research program is to establish a platform targeting protein arginine methyltransferases (PRMTs) that develops small-molecule probes to investigate PRMTs as viable therapeutic targets and to provide lead compounds toward developing PRMT-based new diagnosis and treatment in cancers. The objective of this proposal is to validate a general structure-based approach for developing inhibitors of various PRMTs and to identify selective small-molecule inhibitors of CARM1 for investigating therapeutic potentials of chemical inhibition of CARM1 in cancer. The proposed approach builds upon our existing expertise in synthetic chemistry, assay development, and molecular and cell biology, and leverages our strong collaboration with experts in cancer biology, computation and proteomics. The central hypothesis of this proposal is that small molecules could modulate the function of specific PRMTs by interfering the selective binding of individual PRMT with co-factor SAM methyl donor or arginine substrate. To accomplish the objective of this application the following two specific aims will be pursued. Aim 1) Construct a collection of SAM-mimic and arginine mimic compounds targeting chemical inhibition of PRMTs. Aim 2) Identify CARM1 inhibitors and validate therapeutic potentials of chemical inhibition of CARM1 in cancers. Through this exploratory grant, the identification of novel small-molecule inhibitors of CARM1 will validate the general applicability of the proposed structure-based approach for developing inhibitors for various PRMTs of promising cancer-therapeutic targets. Furthermore, the identified small-molecule inhibitors of CARM1 will, for the first time, provide cell-active lead compounds for the discovery of new diagnostic biomarkers and therapeutic treatment for CARM1-assoscaited breast and prostate cancers.